The present invention relates to the synthesis of guanidine compounds such as the anti-diabetic compound linogliride or N-(1-methyl-2-pyrrolidinylidene)-N'-phenyl-4-morpholinecarboximidamide and includes synthetic steps and intermediates.
Linogliride fumarate (CAS Registry No. 78782-47-5) is a hypoglycemic compound and is disclosed in U.S. Pat. No. 4,211,867. It is an object of the present invention to provide a high yield, facile and short synthesis of linogliride with byproducts and reagents which are comparatively safe and easily handled.
At column 11 of U.S. Pat. No. 4,211,867 there is described a method of making an N,N'-disubstituted guanidine intermediate by reacting an N-substituted thiourea with an alkylating agent to produce the corresponding alkylthio compound which is then reacted with an amine to displace a mercaptan. Such a route has the disadvantage of removal and disposal of odoriferous mercaptans.
Oxidations of thioureas are found in U.S. Pat. Nos. 4,210,658, 4,265,896 and 4,381,395, U.K. Pat. No. 1,587,258, U.S.S.R. Pat. No. 178,803 published Feb. 3, 1966 and by W. Walter and G. Randau in Liebigs Ann. Chem. 722, pages 98-109 (1969).